A processive rotary mechanism couples substrate unfolding and proteolysis in the ClpXP degradation machinery
- University of Toronto, Canada
Abstract
The ClpXP degradation machine consists of a hexameric AAA+ unfoldase (ClpX) and a pair of heptameric serine protease rings (ClpP) that unfold, translocate, and subsequently degrade client proteins. ClpXP is an important target for drug development against infectious diseases. Although structures are available for isolated ClpX and ClpP rings, it remains unknown how symmetry mismatched ClpX and ClpP work in tandem for processive substrate translocation into the ClpP proteolytic chamber. Here we present cryo-EM structures of the substrate-bound ClpXP complex from Neisseria meningitidis at 2.3 to 3.3 Å resolution. The structures allow development of a model in which the sequential hydrolysis of ATP is coupled to motions of ClpX loops that lead to directional substrate translocation and ClpX rotation relative to ClpP. Our data add to the growing body of evidence that AAA+ molecular machines generate translocating forces by a common mechanism.
Data availability
CryoEM maps and models have been deposited in the EMDB and PDB.
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Maps NmClpXP Conformation AElectron Microscopy Data Bank, EMD-21187.
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Maps NmClpXP Conformation BElectron Microscopy Data Bank, EMD-21194.
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Maps NmClpXP D7Electron Microscopy Data Bank, EMD-21195.
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Maps Apo-NmClpPElectron Microscopy Data Bank, EMD-21196.
Article and author information
Author details
Funding
Canadian Institutes of Health Research (FDN-503573)
- Lewis E Kay
Canadian Institutes of Health Research (PJT-162186)
- John L Rubinstein
Canadian Institutes of Health Research (PJT-148564)
- Walid A Houry
Canadian Institutes of Health Research
- Zev A Ripstein
Canadian Institutes of Health Research
- Siavash Vahidi
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Axel T Brunger, Stanford University, United States
Version history
- Received: September 24, 2019
- Accepted: January 8, 2020
- Accepted Manuscript published: January 9, 2020 (version 1)
- Version of Record published: April 1, 2020 (version 2)
Copyright
© 2020, Ripstein et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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A processive rotary mechanism couples substrate unfolding and proteolysis in the ClpXP degradation machinery
eLife 9:e52158.
https://doi.org/10.7554/eLife.52158
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